• Cesar Sommer, Bijan Boldajipour, Tracy C Kuo, Trevor Bentley, Janette Sutton, Amy Chen, Tao Geng, Holly Dong, Roman Galetto, Julien Valton, Thomas Pertel, Alexandre Juillerat, Annabelle Gariboldi, Edward Pascua, Colleen Brown, Sherman M Chin, Tao Sai, Yajin Ni, Philippe Duchateau, Julianne Smith, Arvind Rajpal, Thomas Van Blarcom, Javier Chaparro-Riggers, and Barbra J Sasu.
• Allogene Therapeutics, Inc., 210 E. Grand Avenue, South San Francisco, CA 94080, USA. Electronic address: cesar.sommer@allogene.com.
• Mol. Ther. 2019 Jun 5; 27 (6): 1126-1138.

AbstractClinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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